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Intellectual disability

Gene: TFE3

Amber List (moderate evidence)

TFE3 (transcription factor binding to IGHM enhancer 3)
EnsemblGeneIds (GRCh38): ENSG00000068323
EnsemblGeneIds (GRCh37): ENSG00000068323
OMIM: 314310, Gene2Phenotype
TFE3 is in 3 panels

2 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 16 Nov 2020, 3:34 p.m. | Last Modified: 16 Nov 2020, 3:34 p.m.
Panel Version: 3.542
Not associated with a relevant phenotype in OMIM, but as a confirmed Gen2Phen gene for X-linked dominant Intellectual disability with pigmentary mosaicism and storage disorder and hemizygous TFE3-related intellectual disability with pigmentary mosaicism. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no relevant OMIM or MONDO title as of 16/11/2020).
Created: 16 Nov 2020, 3:28 p.m. | Last Modified: 16 Nov 2020, 3:36 p.m.
Panel Version: 3.542

Konstantinos Varvagiannis (Other)

Green List (high evidence)

[This gene was present in the ID panel with red rating, though with no reviews].

7 unrelated individuals with de novo TFE3 pathogenic variants have been reported in the following studies:

[1] Villegas et al (2019 - PMID: 30595499) - Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3 [5 individuals]
[2] Diaz et al (2019 - PMID: 31833172) - TFE3-associated neurodevelopmental disorder: A distinct recognizable syndrome [2 additional individuals]

Overlapping features observed in almost all included DD and severe ID (7/7), coarse facial features (6/7) as well as blaschkoid pigmentary mosaicism (6/7). Epilepsy was reported in 5/7. Variable other features observed in some/few included (by decreasing order of frequency): hypotonia, developmental regression, obesity, hand stereotypies, hepatomegaly, umbilical hernia, ASD, recurrent otitis media, hypoglycemia, etc.

TFE3 encodes transcription factor for immunoglobulin heavy-chain enhancer 3. The gene lies on Xp11.23.

All individuals reported to date have been found to harbor de novo variants affecting exons 3 or 4. Six different missense variants have been reported. A suspected ectopic nuclear gain-of-function effect has been proposed in Ref1. One additional similarly affected individual harbored a canonical splice site variant (NM_006521.4:c.780+1G>A in intron 4) predicted to lead to in-frame skipping of exon 4 (Ref2).

6/7 affected individuals were females. Random X-chromosome inactivation (XCI) was shown for an individual with blaschkoid pigmentary mosaicism. It has been commented and shown that the (single) female without BPM had skewed XCI (Ref1).

A single male was also affected. This individual harbored a de novo mosaic variant (65% in blood) (Ref1).

Previous investigations included among others:
- metabolic work-up in some individuals (Refs1/2), also for suspected lysosomal disorders (due to coarse facial features, hepatomegaly, hypoglycemia, etc)
- conventional karyotype in some cases (for one individual a mosaic t(X;11) with Xp22.3 microdeletion was demonstrated in Ref1, but this did not contain genes for ID/epilepsy reason why WES was subsequently pursued)
- SNP-CMA (skin & blood or skin only - for the 2 individuals in Ref2)
- For individuals from Ref2 variable IKBKG genetic testing, testing for Angelmann/Beckwith-Wiedemann syndrome, ID/epilepsy/ASD gene panel testing was carried out.

Exome sequencing in some cases in Ref2 revealed additional de novo variants in other genes not thought to contribute to the phenotype due to the inheritance mode (AR with absence of other variant in trans) or due to in silico predictions predicting a tolerated/benign effect for the respective variant(s) (eg. for NCOR1).

To the best of my understanding (?) and better summarized by VanHook AM (2019 - DOI: 10.1126/scisignal.aax0926 - ):
Sequestering of Tfe3 in the cytoplasm (through recruitment to the lysosomal membrane) prevents its role as transcription factor in the nucleus. Mutations preventing its recruitment to lysosomes, prevent cytoplasmic sequestration, enabling Tfe3 to enter the nucleus and in turn affect (/block) stem cell differentiation. Exons 3 and 4 are suggested to form a structure important for cytoplasmic Tfe3 inactivation. Villegas et al studied Tfe3 KO embryonic stem cells (ESCs) expressing murine alleles (Q118P and P185L) corresponding to mutations observed in affected individuals (Q119P/P186L). The variants were shown to affect Tfe3 localization (/induce nuclear localization) and prevent spontaneous differentiation of ESCs into neural progenitors. Signalling pathways and functional effects (as proposed by Villegas et al) are summarized in the reference above.
Created: 27 Dec 2019, 10:49 p.m. | Last Modified: 27 Dec 2019, 10:49 p.m.
Panel Version: 3.0

Mode of inheritance

Global developmental delay; Intellectual disability; Abnormality of skin pigmentation; Coarse facial features; Seizures


Mode of pathogenicity


Mode of Inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
  • Expert Review Amber
  • Victorian Clinical Genetics Services
  • TFE3-related intellectual disability with pigmentary mosaicism
for-review Skewed X-inactivation
Clinvar variants
Variants in TFE3
Panels with this gene

History Filter Activity

2 Dec 2020, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Skewed X-inactivation tag was added to gene: TFE3.

2 Dec 2020, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism

2 Dec 2020, Gel status: 2

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: TFE3 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

16 Nov 2020, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: tfe3 has been classified as Amber List (Moderate Evidence).

16 Nov 2020, Gel status: 1

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: TFE3 were set to

16 Nov 2020, Gel status: 1

Added Tag

Sarah Leigh (Genomics England Curator)

Tag for-review tag was added to gene: TFE3.

29 Sep 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance

Louise Daugherty (Genomics England Curator)

gene: TFE3 was added gene: TFE3 was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: TFE3 was set to